The pancreas is formed by exocrine tissue and by endocrine cells which form the islets of Langherans. Although it is generally agreed that pancreatic cells are derived from the endoderm, questions concerning the origin of the cells were again raised when it was discovered that some endocrine cells express catecholamine enzymes, a typical neuronal trait. In this research proposal we will test the hypothesis that the expression of catecholamine enzymes by endocrine cells in not a reflection of their site of origin but of a stage in the biochemical maturation of pancreatic endocrine cells. We will also seek to determine b) whether the appearance of catecholamine enzymes in endocrine cells of the pancreas is predetermined or if it is influenced by the environment and c) whether pancreatic cells originate from common or separate precursors and if the precursors for the various endocrine cell types express catecholamine enzymes during development. We will also test the hypothesis that endocrine cells containing catecholamine enzyme, being a precursor population, are able to proliferate and increase the amount of islet tissue. The criteria of differentiation will be the immunohistochemical labeling of islet cells with antibodies against pancreatic hormones and catecholamine enzymes. Techniques devised to label two antigens in the same cell will be employed for the cell lineage analysis. Organotypic and cell culture will be used to analyze the role of the environment in the regulation of TH and peptide hormones expression. Finally, the hypothesis that islet growth is produced by proliferation of the peptide cells containing TH will be tested in mutant obese mice, animals that develop hyperplastic islets, and in B-cell tumors of transgenic mice.